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Neutrophilic myeloperoxidase-macrophage interactions perpetuate chronic inflammation associated with experimental
D L Lefkowitz1, M P Gelderman, S R Fuhrmann
1Texas Tech University, Lubbock, Texas 79409, USA.
Abstract:
Rheumatoid arthritis is a systemic disease of unknown etiology. The purpose of this study was to elucidate an unrecognized interaction between neutrophilic myeloperoxidase (MPO) and macrophages (Mphi) which could perpetuate the inflammatory response associated with arthritis. A monoarticular arthritis was induced by intra-articular injection of group A streptococcus cell wall fragments (PG-APS) into the ankle joint of female Lewis rats. After swelling/erythema subsided, joints were reinjected with either recombinant MPO or enzymatically inactive MPO (iMPO). Joint measurements were made daily and arthritis was confirmed by histology. Neither iMPO nor MPO could initiate "clinical" arthritis; however, either form of the enzyme injected after PG-APS induced a dose-dependent increase in erythema and swelling. Mannans, which block the binding of MPO to Mo, ablated clinical symptoms. Also, the presence of tumor necrosis factor alpha was observed only in diseased joints using immunocytochemistry.
Insights
Myeloperoxidase (MPO) and macrophages (Mphi) interaction exacerbates rheumatoid arthritis inflammation. Mannans blocking MPO binding to Mphi reduced symptoms, revealing a key inflammatory pathway.
Area of Science:
- Immunology
- Rheumatology
- Biochemistry
Background:
- Rheumatoid arthritis (RA) is a systemic autoimmune disease with unknown causes.
- Chronic inflammation in RA involves complex interactions between immune cells and mediators.
- Neutrophilic myeloperoxidase (MPO) is an enzyme implicated in inflammatory processes.
Purpose of the Study:
- To investigate the role of neutrophilic myeloperoxidase (MPO) in perpetuating inflammation in rheumatoid arthritis.
- To elucidate the interaction between MPO and macrophages (Mphi) in the context of arthritis.
Main Methods:
- Monoarticular arthritis was induced in Lewis rats using group A streptococcus cell wall fragments (PG-APS).
- Recombinant MPO or inactive MPO (iMPO) was injected into joints after initial inflammation subsided.
- Clinical symptoms (swelling, erythema) were measured daily, and arthritis was confirmed histologically.
- Mannans were used to block MPO binding to macrophages, and tumor necrosis factor alpha (TNF-α) presence was assessed via immunocytochemistry.
Main Results:
- Neither MPO nor iMPO alone initiated arthritis.
- Injection of MPO or iMPO post-PG-APS induced a dose-dependent increase in joint swelling and erythema.
- Mannans significantly reduced clinical arthritis symptoms, indicating MPO-macrophage interaction is crucial.
- Tumor necrosis factor alpha was detected only in diseased joints.
Conclusions:
- Neutrophilic myeloperoxidase (MPO) interaction with macrophages (Mphi) plays a significant role in perpetuating arthritis inflammation.
- Blocking MPO-macrophage binding with Mannans ameliorates arthritis symptoms.
- This interaction, potentially involving TNF-α, represents a novel therapeutic target for rheumatoid arthritis.